1. Field of the Invention
This invention provides novel compounds possessing antibacterial, antifungal and/or antitumor activity. Pharmaceutical compositions containing these compounds, methods of making and methods for using these compounds are also provided.
2. State of the Art
The binding of the antibacterial netropsin and distamycin to AT-rich sequences in the minor groove of double-stranded DNA is a well studied phenomenon. Because such binding can be used to regulate DNA expression, e.g., by blocking and/or displacement of regulatory proteins, or by inhibiting the activity of enzymes acting on DNA, such as reverse transcriptase or topoisomerase, enhancement of this binding has been the subject of numerous recent studies.
As described in a recent review by Bailly and Chaires (Bioconj. Chem. 9(5):513-38, 1998), the pyrrolecarboxamide unit in netropsin and distamycin is actually about 20% longer than required to perfectly match the corresponding base pair sequence in the minor groove. Accordingly, in oligomeric analogs having multiple binding moieties, successive binding moieties can become out of phase with the base pairs of the minor groove. Several studies have therefore been directed to dimers of netropsin or distamycin containing different linkers, in order to improve binding to longer target sequences. In these reports, effectiveness of various netropsin or distamycin dimers was determined, for example, in the inhibition of transcription by HIV-1 reverse transcriptase (M. Filipowsky et al., Biochemistry 35:15397-410, 1996), inhibition of mammalian DNA topoisomerase I (Z. Wang et al., Biochem. Pharmacol. 53:309-16, 1997), or inhibition of HIV 1 integrase (N. Neamati et al., Mol. Pharmacol. 54:280-90, 1998).
Preferred linkers in these studies included p-phenylene, trans-vinyl, cyclopropyl, 3,5-pyridyl, and six- and eight-carbon aliphatic chains. Several of these linkers restrict rotation around the linking group, thus reducing the extent of purely monodentate binding (e.g. by only one netropsin moiety; see Bailly) which can occur with flexible linkers. However, Kissinger et al. (Chem. Res. Toxicol. 3(2): 162-8, 1990) reported that aryl-linked groups had reduced DNA binding affinity compared to alkyl and alkylene linkers, and Neamati et al. (cited above) reported that the trans-vinyl linked compound was many times more potent (in inhibiting HIV-1 integrase) than the “more rigid” cyclobutanyl and norbornyl linkers. It was suggested in Wang and in Bailly that, for certain applications, the more rigid linkers (cyclopropyl and p-phenylene) may not allow for optimal simultaneous (bidentate) binding of the two netropsin moieties flanking the linker. Therefore, it would be desirable to provide linkers which reduce monodentate binding but which provide suitable geometries for bidentate binding. Nevertheless, there is much confusion as to what constitutes linkers of choice such that highly active anti-bacterial compounds are formed.
Broadly, known antibacterial compounds work by influencing at least one of the following: cell wall synthesis, protein synthesis, nucleic acid synthesis, cellular metabolism and cytoplasmic membrane permeability. However, increasing resistance of bacteria to antibiotics has brought renewed attention to the development of new compounds that react against a broad array of common bacterial pathogens. Further, there has been increasing incidences of systematic fungal infections. The increase could be attributed to the chronic use of antimicrobial agents, lending to the realization that there is a need for new compounds to combat such infections. The compounds of the present invention fulfill this need.